A human exocervical cell line that became tumorigenic after sequential transfection with human papillomavirus (HPV) 16 and an activated v-Ha-ras oncogene had HPV sequences on chromosome 21 near ets-2 proto-oncogene. HPV-16 insertion at this site was implicated in the formation of a homogeneously staining region, an alteration indicative of gene amplification that may be essential to the acquisition of cell immortality. HPVs associated with invasive cancer, adeno-12, Epstein-Barr, hepatitis-B and simian-40 viruses integrate at referential sites on the human genome. Fifty-one percent of 35 regionally localized integration sites of five DNA viruses correspond to the location of fragile sites and proto-oncogenes. Two proto-oncogenes, erbB-3 and dbl, two genes coding for nonhistone chromosomal protein, and a cluster of Cathepsin G-like genes were localized at regions of major interest on the human genome. ErbB-3 was mapped to chromosome 12qll-13 in close proximity to Int-1 and GLI proto-oncogenes. Dbl gene was localized on chromosome Xq27, a region that may be important for further defining the molecular alterations associated with chromosome fragility and X-linked mental retardation. HMG-14 and HMG-17 genes for nonhistone chromosomal protein were mapped on chromosomes 2lq22.3 and lp36.1, respectively. HMG-14 gene is located at the region considered critical for Down's syndrome. Cathepsin-G gene and a cathepsin G-like gene were mapped on chromosome 14 at band q11.2 near alpha and delta T-cell receptor gene, a site involved in most translocations in T-cell neoplasia.